BACKGROUND & AIMS The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, which plays an important role in the maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 in FH pathogenesis. METHODS Msr1-deficient (Msr1-/-) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion. RESULTS Our results showed that Msr1-/- mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type and Msr1-/- mice, suggesting that C5a-induced pro-inflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal-regulated kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection. CONCLUSIONS Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and subsequent complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH. LAY SUMMARY Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH.

中文翻译：

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巨噬细胞清道夫受体 1 通过中性粒细胞介导的补体激活参与暴发性肝炎的发病机制

背景与目的巨噬细胞清道夫受体1（Msr1，也称为SRA）是一种主要表达在骨髓细胞上的模式识别受体，在维持免疫稳态中起重要作用。由于 MSR1 表达在暴发性肝炎 (FH) 患者的肝脏中上调，我们研究了 Msr1 在 FH 发病机制中的功能机制。方法 用小鼠肝炎病毒 A59 株（MHV-A59）感染 Msr1 缺陷（Msr1-/-）小鼠及其野生型（WT）同窝小鼠诱导 FH，检测组织损伤水平、血清丙氨酸转氨酶、炎症测量并比较细胞因子和补体成分 5a (C5a)。研究了 MHV 感染后有或没有中性粒细胞耗竭的肝损伤。结果 我们的结果表明，Msr1-/- 小鼠对MHV 诱导的肝炎具有抗性。用 C5a 受体拮抗剂 (C5aRa) 治疗减少了 MHV 感染的野生型和 Msr1-/- 小鼠之间炎症反应和肝损伤的差异，表明 C5a 诱导的促炎症反应在 Msr1 介导的FH 发病机制的调控。我们证明，在 MHV-A59 刺激下，Msr1 有效增强了中性粒细胞中转化生长因子激活的激酶 1 磷酸化，从而促进了细胞外信号调节激酶途径的激活和随后的 NETosis 形成。此外，我们提供了证据表明阻断 Msr1 可以减轻 MHV-A59 感染引起的肝损伤。结论 Msr1 通过增强中性粒细胞 NETosis 的诱导和随后的补体激活来促进病毒诱导的 FH 的发病机制。靶向 Msr1 可用作 FH 的新免疫治疗策略。概述 病毒引起的暴发性肝炎 (FH) 是一种在世界范围内死亡率很高的疾病。FH 和小鼠实验性 FH 患者肝脏中巨噬细胞清道夫受体 1 (Msr1) 水平升高表明 Msr1 在 FH 的发病机制中起作用。在此，我们证明了 Msr1 缺陷的小鼠对 MHV-A59 诱导的 FH 具有抗性，并且 Msr1 抑制剂岩藻依聚糖抑制小鼠 FH 的进展。我们的研究表明，使用抑制 MSR1 功能的药物可能对 FH 患者有益。FH 和小鼠实验性 FH 患者肝脏中巨噬细胞清道夫受体 1 (Msr1) 水平升高表明 Msr1 在 FH 的发病机制中起作用。在此，我们证明了 Msr1 缺陷的小鼠对 MHV-A59 诱导的 FH 具有抗性，并且 Msr1 抑制剂岩藻依聚糖抑制小鼠 FH 的进展。我们的研究表明，使用抑制 MSR1 功能的药物可能对 FH 患者有益。FH 和小鼠实验性 FH 患者肝脏中巨噬细胞清道夫受体 1 (Msr1) 水平升高表明 Msr1 在 FH 的发病机制中起作用。在此，我们证明了 Msr1 缺陷的小鼠对 MHV-A59 诱导的 FH 具有抗性，并且 Msr1 抑制剂岩藻依聚糖抑制小鼠 FH 的进展。我们的研究表明，使用抑制 MSR1 功能的药物可能对 FH 患者有益。